Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to cancer. We are developing molecular methods based on the polymerase chain reaction (PCR) to detect DNA sequence polymorphisms in four genes (glutathione transferase mu [GST1], debrisoquine hydroxylase [CYP2D6], aryl hydrocarbon hydroxylase (CYP1A1], n-acetyl transferase [NAT2]) that are associated with increased risk of cancer at various tumor sites. For the GST1 gene, we have analyzed 46 individuals and found that PCr genotyping is consistent with lymphocyte enzyme activity. The distribution of high risk (deleted) genotype varies by ethnic background. It was observed in 54% of a N. Carolina cohort and 30% in a Finnish cohort. We are genotyping control and carcinogen-exposed populations and are investigating how high and low risk genotypes modulate the level of DNA damage (DNA adducts, mutation frequency at HPRT, GPA, HLA-A,L SCE, chromosome aberrations) in lymphocytes. Exposed study populations include foundry and textile dye workers, cigarette smokers, and aflatoxin B1-expose individuals from Taiwan. We are also studying the association between high and lo risk genotypes, carcinogen exposure and tumor incidence in the bladder, low risk genotypes, carcinogen exposures liver an lung.